Crigler-Najjar syndrome isaconditionassociatedwithmutationsinthehepatocyteenzymeUGT.IntypeICrigler-Najjarsyndrome,acongenitalmissensemutationresultsincompletelackofthisenzyme,whereaspatientswithtypeIICrigler-NajjarsyndromehaveamildermutationthatreducesUGTlevelstoabout10%ofthoseseeninnormalindividuals.Thuswithvaryingdegreesofseverity,Crigler-Najjarsyndromeimpairstheabilityofhepatocytestoconjugatebilirubin.Theunconjugatedbilirubinregurgitatesbackintothecirculationandbindstoalbumin,withanassociatedriskofneurologicalinjuryiflevelsriseprecipitously.TheonlyeffectivetreatmentoftypeICrigler-Najjarsyndromeatpresentislivertransplantation,althoughgenetherapymaybeapromisingoptioninthenearfuture.ThosewithtypeIIdiseasecansometimesbemanagedeffectivelywithbluelight.Thisconvertscirculatingunconjugatedbilirubintoformsthataremorewatersolubleandthuslessfirmlyboundtoalbumin,whichcanbeexcretedinurine.
Ammonia Handling by the Liver
Ammonia (NH3) is a small neutral metabolite that arises from protein catabolism and bacterial activity and is highly membrane permeant. The liver is a critical contributor to prevention of ammonia accumulation in the circulation, which is important because like bilirubin, ammonia is toxic to the central nervous system. The liver eliminates ammonia from the body by converting it to urea via a series of enzymatic reactions known as the urea, or Krebs-Henseleit, cycle (Fig. 32.14 ). The liver is the only tissue in the body that can convert ammonia to urea.
Ammonia is derived from two major sources. Approximately 50% is produced in the colon by bacterial ureases. Because the colonic lumen is normally slightly acidic, some of this ammonia is converted to the ammonium ion (NH4 +), which renders it impermeant to the colonic epithelium and therefore allows it to be excreted in stool. However, the remainder of the ammonia generated crosses the colonic epithelium passively and is transported to the liver via the portal circulation. The other major source of ammonia (≈40%) is the kidney (see ). A small amount of ammonia (≈10%) is derived from deamination of amino acids in the liver, by metabolic processes in muscle cells, and via release of glutamine from senescent red blood cells.
The “mass balance” for ammonia handling in a healthy adult is presented in
Fig. 32.15 . As just noted, ammonia is a small neutral molecule that readily crosses cell membranes without the benefit of a specific transporter, although some membrane proteins transport ammonia, including certain aquaporins. Whatever the mechanism for transport, the physicochemical properties of ammonia ensure that it is efficiently extracted from portal and systemic circulation •Fig. 32.14 Theureacycle.ADP,adenosinediphosphate;ATP,adenosinetriphosphate.
If the metabolic capacity of the liver is compromised acutely, coma and death can rapidly ensue. In chronic liver disease, patients may experience a gradual decline in mental function that reflects the action of both ammonia and other toxins that cannot be cleared by the liver, in a condition known as hepatic encephalopathy. Development of confusion, dementia, and eventually coma in a patient with liver disease is evidence of significant progression, and these symptoms can prove fatal if left untreated.
Clinical Assessment of Liver Function